The cytokine TWEAK modulates renal tubulointerstitial inflammation.
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ABSTRACT:
SUBMITTER: Sanz AB
PROVIDER: S-EPMC2390965 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing peritonitis. An improved understanding of the molecular contributors to peritoneal injury and defense may increase the therapeutic armamentarium to optimize peritoneal defenses while minimizing peritoneal injury. There is no information on the expression and function of the cytokine TWEAK and its receptor Fn14 during peritoneal injury. Fn14 expression and soluble TWEAK levels were measured in human PD peritoneal effluent cells or fluids with or without peritonitis. Fn14 expression was also analyzed in peritoneal biopsies from PD patients. Actions of intraperitoneal TWEAK were studied in mice in vivo. sTWEAK levels were increased in peritoneal effluent in PD peritonitis. Effluent sTWEAK levels correlated with the number of peritoneal macrophages (r=0.491, p=0.002). Potential TWEAK targets that express the receptor Fn14 include mesothelial cells and macrophages, as demonstrated by flow cytometry of peritoneal effluents and by analysis of peritoneal biopsies. Peritoneal biopsy Fn14 correlated with mesothelial injury, fibrosis and inflammation, suggesting a potential deleterious effect of TWEAK/Fn14. In this regard, intraperitoneal TWEAK administration to mice promoted peritoneal inflammation characterized by increased peritoneal effluent MCP-1, Fn14 and Gr1+ macrophages, increased mesothelial Fn14, MCP-1 and CCL21 expression and submesothelial tissue macrophage recruitment. Taken together these data suggest that the TWEAK/Fn14 system may promote inflammation and tissue injury during peritonitis and PD.
| S-EPMC3944020 | biostudies-literature
Project description:Renal tubulointerstitial damage is the final common pathway leading from chronic kidney disease to end-stage renal disease. Inflammation is clearly involved in tubulointerstitial injury, but it remains unclear how the inflammatory processes are initiated and regulated. Here, we have shown that in the mouse kidney, the transcription factor Krüppel-like factor-5 (KLF5) is mainly expressed in collecting duct epithelial cells and that Klf5 haploinsufficient mice (Klf5+/- mice) exhibit ameliorated renal injury in the unilateral ureteral obstruction (UUO) model of tubulointerstitial disease. Additionally, Klf5 haploinsufficiency reduced accumulation of CD11b+ F4/80(lo) cells, which expressed proinflammatory cytokines and induced apoptosis among renal epithelial cells, phenotypes indicative of M1-type macrophages. By contrast, it increased accumulation of CD11b+ F4/80(hi) macrophages, which expressed CD206 and CD301 and contributed to fibrosis, in part via TGF-β production--phenotypes indicative of M2-type macrophages. Interestingly, KLF5, in concert with C/EBPα, was found to induce expression of the chemotactic proteins S100A8 and S100A9, which recruited inflammatory monocytes to the kidneys and promoted their activation into M1-type macrophages. Finally, assessing the effects of bone marrow-specific Klf5 haploinsufficiency or collecting duct- or myeloid cell-specific Klf5 deletion confirmed that collecting duct expression of Klf5 is essential for inflammatory responses to UUO. Taken together, our results demonstrate that the renal collecting duct plays a pivotal role in the initiation and progression of tubulointerstitial inflammation.
| S-EPMC3163964 | biostudies-literature
Project description:Acute tubulointerstitial nephritis (ATIN) diagnosis lays on histological assessment through a kidney biopsy, given the absence of accurate non-invasive biomarkers. The aim of this study was to evaluate the accuracy of different urinary inflammation-related cytokines for the diagnostic of ATIN and its distinction from acute tubular necrosis (ATN). We included 33 patients (ATIN (n = 21), ATN (n = 12)), and 6 healthy controls (HC). We determined the urinary levels of 10 inflammation-related cytokines using a multiplex bead-based Luminex assay at the time of biopsy and after therapy, and registered main clinical, analytical and histological data. At the time of biopsy, urinary levels of I-TAC/CXCL11, CXCL10, IL-6, TNFα and MCP-1 were significantly higher in ATIN compared to HC. A positive correlation between the extent of the tubulointerstitial cellular infiltrates in kidney biopsies and the urinary concentration of I-TAC/CXCL11, MIG/CXCL9, CXCL10, IL17, IFNα, MCP1 and EGF was observed. Notably, I-TAC/CXCL11, IL-6 and MCP-1 were significantly higher in ATIN than in ATN, with I-TAC/CXCL11 as the best discriminative classifier AUC (0.77, 95% CI 0.57-0.95, p = 0.02). A combinatory model of these three urinary cytokines increased the accuracy in the distinction of ATIN/ATN compared to the individual biomarkers. The best model resulted when combining the three cytokines with blood eosinophil and urinary leukocyte counts (LR = 9.76). Follow-up samples from 11ATIN patients showed a significant decrease in I-TAC/CXCL11, MIG/CXCL9 and CXCL10 levels. Urinary I-TAC/CXCL11, CXCL10, IL6 and MCP-1 levels accurately distinguish patients developing ATIN from ATN and healthy individuals and may serve as novel non-invasive biomarkers in this disease.
| S-EPMC8268986 | biostudies-literature
Project description:Renal tubulointerstitial inflammation has an important role in fibrosis, which is the main pathogenetic alteration associated with chronic kidney disease (CKD). The left‑right determination factor 1 (Lefty‑1) gene pleiotropically and biologically regulates transforming growth factor, mitogen‑activated protein kinase and other signaling pathways, and is considered to have a potential anti‑inflammatory function. However, its role in renal tubulointerstitial inflammation, which is often a long‑term consequence of renal fibrosis, is currently unknown. In the present study, the effects of adenovirus‑mediated overexpression of Lefty‑1 (Ad‑Lefty‑1‑flag) on renal tubulointerstitial inflammation were determined using a mouse model of unilateral ureteral obstruction (UUO) and a rat renal tubular duct epithelial cell line (NRK‑52E), which was treated with lipopolysaccharide (LPS). In vivo results indicated that the inflammatory response was increased in UUO mice, as evidenced by the increase in inflammatory cytokines and chemokines. Conversely, Lefty‑1 significantly reversed the effects of UUO. Furthermore, the results of the in vitro study demonstrated that Lefty‑1 significantly inhibited LPS‑induced inflammatory marker expression in cultured NRK‑52E cells via the nuclear factor (NF)‑κB signaling pathway. These results suggested that Lefty‑1 may ameliorate renal tubulointerstitial inflammation by suppressing NF‑κB signaling. In conclusion, the findings of the present study indicated that Lefty‑1 may be considered a potential novel therapeutic agent for inhibiting renal tubulointerstitial inflammation or even reversing the CKD process.
| S-EPMC5819905 | biostudies-literature
Project description:Renal parenchymal inflammation is a critical determinant of kidney injury in renal artery stenosis (RAS) but is difficult to assess in the single kidney without tissue samples. Whether renal vein (RV) levels of inflammatory markers reflect active parenchymal inflammation remains unknown. We evaluated the relationship between net RV cytokine release and tissue inflammation in the post-stenotic kidney.Pigs were studied after 10 weeks of RAS treated 4 weeks earlier with intra-renal vehicle or anti-inflammatory mesenchymal stem cells (MSCs) or normal control. Single-kidney renal blood flow was measured by fast computerized tomography. RV and inferior vena cava levels of tumor necrosis factor (TNF)-?, interferon (IF)-?, monocyte chemoattractant protein (MCP-1) and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay, and their net release calculated. Renal expression of the same cytokines was correlated with their net release.Net release of TNF-?, IF-? and MCP-1 was higher in RAS compared with normal and to the contralateral kidney (all P<0.05), decreased in MSC-treated pigs as was their tissue expression. Contrarily, the release of the anti-inflammatory IL-10 was lower in RAS and normalized in RAS+MSC. The net release of TNF-?, MCP-1 and IL-10 directly correlated with their tissue expression. The ratio of inflammatory-to-reparative macrophages directly correlated with the release of MCP-1, but inversely with the release of IL-10. In vitro cultured MSCs also induced a shift in the macrophage phenotype from inflammatory (M1) to reparative (M2).Our findings demonstrate that the release of inflammatory markers from the affected kidney provides an index of renal tissue inflammation in experimental RAS.
| S-EPMC3910338 | biostudies-literature
Project description:Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) activates the fibroblast growth factor-inducible-14 (Fn14) receptor. TWEAK has actions on intrinsic kidney cells and on inflammatory cells of potential pathophysiological relevance. The effects of TWEAK in tubular cells have been explored in most detail. In cultured murine tubular cells TWEAK induces the expression of inflammatory cytokines, downregulates the expression of Klotho, is mitogenic, and in the presence of sensitizing agents promotes apoptosis. Similar actions were observed on glomerular mesangial cells. In vivo TWEAK actions on healthy kidneys mimic cell culture observations. Increased expression of TWEAK and Fn14 was reported in human and experimental acute and chronic kidney injury. The role of TWEAK/Fn14 in kidney injury has been demonstrated in non-inflammatory compensatory renal growth, acute kidney injury and chronic kidney disease of immune and non-immune origin, including hyperlipidaemic nephropathy, lupus nephritis (LN) and anti-GBM nephritis. The nephroprotective effect of TWEAK or Fn14 targeting in immune-mediated kidney injury is the result of protection from TWEAK-induced injury of renal intrinsic cells, not from interference with the immune response. A phase I dose-ranging clinical trial demonstrated the safety of anti-TWEAK antibodies in humans. A phase II randomized placebo-controlled clinical trial exploring the efficacy, safety and tolerability of neutralizing anti-TWEAK antibodies as a tissue protection strategy in LN is ongoing. The eventual success of this trial may expand the range of kidney diseases in which TWEAK targeting should be explored.
| S-EPMC3968810 | biostudies-literature
Project description:Atopic dermatitis (AD) and psoriasis are driven by alternate type 2 and type 17 immune responses, but some proteins might be critical to both diseases. Here we show that a deficiency of the TNF superfamily molecule TWEAK (TNFSF12) in mice results in defective maintenance of AD-specific T helper type 2 (Th2) and psoriasis-specific Th17 cells in the skin, and impaired expression of disease-characteristic chemokines and cytokines, such as CCL17 and TSLP in AD, and CCL20 and IL-19 in psoriasis. The TWEAK receptor, Fn14, is upregulated in keratinocytes and dermal fibroblasts, and TWEAK induces these cytokines and chemokines alone and in synergy with the signature T helper cytokines of either disease, IL-13 and IL-17. Furthermore, subcutaneous injection of recombinant TWEAK into naive mice induces cutaneous inflammation with histological and molecular signs of both diseases. TWEAK is therefore a critical contributor to skin inflammation and a possible therapeutic target in AD and psoriasis.
| S-EPMC5493595 | biostudies-literature
Project description:The tumour necrosis factor (TNF) family member TWEAK activates the Fn14 receptor and has pro-apoptotic, proliferative and pro-inflammatory actions that depend on the cell type and the microenvironment. We explored the proliferative actions of TWEAK on cultured tubular cells and in vivo on renal tubules. Additionally, we studied the role of TWEAK in compensatory proliferation following unilateral nephrectomy and in an inflammatory model of acute kidney injury (AKI) induced by a folic acid overdose. TWEAK increased the proliferation, cell number and cyclin D1 expression of cultured tubular cells, in vitro. Exposure to serum increased TWEAK and Fn14 expression and the proliferative response to TWEAK. TWEAK activated the mitogen-activated protein kinases ERK and p38, the phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway and NF-kappaB. TWEAK-induced proliferation was prevented by inhibitors of these protein kinases and by the NF-kappaB inhibitor parthenolide. TWEAK-induced tubular cell proliferation as assessed by PCNA and cyclin D1 expression in the kidneys of adult healthy mice in vivo. By contrast, TWEAK knock-out mice displayed lower tubular cell proliferation in the remnant kidney following unilateral nephrectomy, a non-inflammatory model. This is consistent with TWEAK-induced proliferation on cultured tubular cells in the absence of inflammatory cytokines. Consistent with our previously published data, in the presence of inflammatory cytokines TWEAK promoted apoptosis, not proliferation, of cultured tubular cells. In this regard, TWEAK knock-out mice with AKI displayed less tubular apoptosis and proliferation, as well as improved renal function. In conclusion, TWEAK actions in tubular cells are context dependent. In a non-inflammatory milieu TWEAK induces proliferation of tubular epithelium. This may be relevant for compensatory renal hyperplasia following nephrectomy.
| S-EPMC4516489 | biostudies-literature
Project description:BackgroundAcute tubulointerstitial nephritis (ATIN) is an important cause of acute kidney injury and often a potentially reversible disease. However, the role of steroids in ATIN remains controversial and the underlying mechanisms remain unresolved.MethodsA total of 113 adult patients with biopsy-proven ATIN were recruited from three tertiary referral centers. Of 102 patients with idiopathic or drug-induced ATIN, outcomes such as renal recovery, end-stage renal disease, and all-cause mortality were compared between the steroid-treated and non-treated groups. Plasma and urine inflammatory cytokine levels at the time of biopsy were analyzed in patients (n = 33) using a bead-based multiplex assay and compared with those of healthy individuals (n = 40).ResultsSteroids were used in 92 (81.4%) of the total patients and in 82 (80.3%) patients with idiopathic or drug-induced ATIN. The rate of renal recovery and the risks of end-stage renal disease and mortality were not different between the steroid-treated and non-treated groups. Despite using a propensity score matching method (n = 20 in each group), none of the outcomes were different between the two groups. Several cytokines, such as monocyte chemotactic protein-1, interferon-α, and interleukin-6 and interleukin-8 levels, were markedly elevated in plasma and urine of patients compared with those in healthy individuals. However, cytokines related to Th2 response, such as IL-10, IL-33, were not different between the two groups.ConclusionsSteroid use does not affect the overall outcome of ATIN. Based on the fact that targeting therapy should be investigated to improve outcomes, the present cytokine results will be helpful for developing a novel therapy for ATIN.
| S-EPMC6417076 | biostudies-literature
Project description:Renal tubulointerstitial fibrosis (TIF) is the final pathway of various renal injuries that result in chronic kidney disease. The mammalian Hippo-Salvador signaling pathway has been implicated in the regulation of cell proliferation, cell death, tissue regeneration, and tumorigenesis. Here, we report that the Hippo-Salvador pathway plays a role in disease development in patients with TIF and in a mouse model of TIF. Mice with tubular epithelial cell (TEC)-specific deletions of Sav1 (Salvador homolog 1) exhibited aggravated renal TIF, enhanced epithelial-mesenchymal transition-like phenotypic changes, apoptosis, and proliferation after unilateral ureteral obstruction (UUO). Moreover, Sav1 depletion in TECs increased transforming growth factor (TGF)-? and activated ?-catenin expression after UUO, which likely accounts for the abovementioned enhanced TEC fibrotic phenotype. In addition, TAZ (transcriptional coactivator with PDZ-binding motif), a major downstream effector of the Hippo pathway, was significantly activated in Sav1-knockout mice in vivo. An in vitro study showed that TAZ directly regulates TGF-? and TGF-? receptor II expression. Collectively, our data indicate that the Hippo-Salvador pathway plays a role in the pathogenesis of TIF and that regulating this pathway may be a therapeutic strategy for reducing TIF.
| S-EPMC4994041 | biostudies-literature